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Cutting edge: Inhibition of IL-6 trans-signaling protects from malaria-induced lethality in mice
Claudia M Wunderlich1, Denis Delić, Kristina Behnke
1Center of Molecular Medicine Cologne, Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, Institute for Genetics Cologne, Max Planck Institute for Neurological Research Cologne, D-50931 Cologne, Germany.
Abstract:
Circulating IL-6 levels correlate with the severity of blood-stage malaria in humans and mouse models, but the impact of IL-6 classic signaling through membrane IL-6Rα, as well as IL-6 trans-signaling through soluble IL-6Rα, on the outcome of malaria has remained unknown. In this study, we created IL-6Rα-deficient mice that exhibit a 50% survival of otherwise lethal blood-stage malaria of the genus Plasmodium chabaudi. Inducing IL-6 trans-signaling by injection of mouse recombinant soluble IL-6Rα in IL-6Rα-deficient mice restores the lethal outcome to malaria infection. In contrast, inhibition of IL-6 trans-signaling via injection of recombinant sGP130Fc protein in control mice results in a 40% survival rate. Our data demonstrate that IL-6 trans-signaling, rather than classic IL-6 signaling, contributes to malaria-induced lethality in mice, preceded by an increased inflammatory response. Therefore, inhibition of IL-6 trans-signaling may serve as a novel promising therapeutic basis to combat malaria.
Insights
Interleukin-6 (IL-6) trans-signaling, not classic signaling, drives lethal malaria in mice. Inhibiting this pathway offers a potential new therapeutic strategy for malaria treatment.
Area of Science:
- Immunology
- Infectious Diseases
- Molecular Biology
Background:
- Interleukin-6 (IL-6) levels correlate with malaria severity.
- The distinct roles of IL-6 classic signaling and IL-6 trans-signaling in malaria outcomes were previously unknown.
Purpose of the Study:
- To investigate the specific contribution of IL-6 classic signaling versus IL-6 trans-signaling to malaria lethality.
- To explore the therapeutic potential of targeting IL-6 trans-signaling in malaria.
Main Methods:
- Generation of IL-6 receptor alpha (IL-6Rα)-deficient mice.
- Experimental induction of IL-6 trans-signaling using soluble IL-6Rα.
- Inhibition of IL-6 trans-signaling with a recombinant sGP130Fc protein.
- Assessment of survival rates in Plasmodium chabaudi infected mice.
Main Results:
- IL-6Rα-deficient mice showed 50% survival in a lethal malaria model.
- Restoring IL-6 trans-signaling in deficient mice re-established lethal outcomes.
- Inhibiting IL-6 trans-signaling in control mice increased survival to 40%.
- IL-6 trans-signaling was associated with increased inflammatory responses.
Conclusions:
- IL-6 trans-signaling, mediated by soluble IL-6Rα, is a key driver of malaria-induced lethality in mice.
- Classic IL-6 signaling plays a lesser role in malaria pathogenesis.
- Targeting IL-6 trans-signaling presents a promising therapeutic avenue for combating malaria.
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